Where's the bathroom? Immunofluorescence images show neurons producing P2X3 in mouse bladder tissue (yellow, top image) but not the same tissue in knockout mice (bottom), who also urinated less frequently.

When you injure yourself, a complex molecular signal delivers the "ouch" to your brain. Two new studies show how one protein, known as P2X3, helps transmit that signal. But they also suggest P2X3 could play a role in treating an overactive bladder.

A host of compounds, such as bradykinin and prostaglandins and an energy-rich molecule called ATP, are released to trigger the pain response when we sustain an injury. In 1995, scientists discovered that P2X3, which is found in damage-sensing neurons, allows ions to flow in and out of neuron cells when it binds to ATP. This suggested that P2X3 was also involved in pain, but scientists didn't have proof that it actually carried the pain signal.

To find out, two research groups independently looked at mice engineered to lack P2X3. When they injected normal and altered mice with formalin--a substance known to cause injury and pain--both teams found that the altered mice didn't lick their paws as much as normal mice, indicating the rodents felt less pain.

But the protein also held several surprises. One of the teams, led by John Wood of University College London, found that mice without P2X3 actually had an increased pain response to chronic inflammation. Wood was also surprised to find out that mice without P2X3 reacted less strongly to nonharmful, mild skin warming. Apparently, the protein also plays a role in sensing warmth, he says.

Meanwhile, the other group, led by Debra Cockayne and Anthony Ford of Roche Bioscience in Palo Alto, California, found that mice without P2X3 urinated less frequently and had greater bladder capacity than normal mice. When the bladder stretches as it fills, the bladder's epithelium releases ATP; the authors conclude that this causes P2X3 to trigger a neural signal that says it's time to urinate. The result suggests that blocking P2X3 with a drug may slow down an overactive bladder, the researchers say.

The two papers, both published in the 26 October issue of Nature, represent a "milestone" in understanding how P2X3 influences pain, says Edwin McCleskey of Oregon Health Sciences University in Portland. While P2X3 may be a potential target for treating certain bladder disorders, McCleskey recommends caution: Wood's study suggests that a potentially serious side effect is an extremely painful response to inflammation, he says.